The perceived controllability of negatively-valenced episodic future thinking modulates delay discounting.

Intertemporal decision-making is important for both economy and physical health. Nevertheless, in daily life, individuals tend to prefer immediate and smaller rewards to delayed and larger rewards, which is known as delay discounting (DD). Episodic future thinking (EFT) has been proven to influence DD. However, there is still no inconsistent conclusion on the effect of negative EFT on DD. Considering the perceived controllability of negative EFT may address the issue (Controllability refers to the extent to which progress and result of an event could be controlled by ourselves). In the current study, we manipulated EFT conditions (baseline, neutral EFT, negative-controllable EFT and negative-uncontrollable EFT), delayed time (i.e. 1 week, 1 month, 3 months, 6 months, 1 year and 3 years) and reward magnitude (small, large). We mainly found that when experiencing negative-uncontrollable EFT compared to negative-controllable EFT in the delayed time of 6 months with large rewards, individuals chose more delayed rewards, suggesting that negative-uncontrollable EFT effectively reduced DD under conditions of both large-magnitude reward and longer delayed time. The current study provides new insight for healthy groups on optimising EFT. In that case, individuals are able to gain long-term benefits in financial management and healthcare.

Sub-Nanosheet Induced Inverse Growth of Negative Valency Au Clusters for Tumor Treatment by Enhanced Oxidative Stress.

Cluster aggregation states are thermodynamically favored at the subnanoscale, for which an inverse growth from nanoparticles to clusters may be realized on subnanometer supports. Herein, we develop Au-polyoxometalate-layered double hydroxide (Au-POM-LDH) sub-1 nm nanosheets (Sub-APL) based on the above strategy, where sub-1 nm Au clusters with negative valence are generated by the in situ disintegration of Au nanoparticles on POM-LDH supports. Sub-1 nm Au clusters with ultrahigh surface atom ratios exhibit remarkable efficiency for glutathione (GSH) depletion. The closely connected sub-1 nm Au with negative valence and POM hetero-units can promote the separation of hole-electrons, resulting in the enhanced reactive oxygen species (ROS) generation under ultrasound (US). Besides, the reversible redox of Mo in POM is able to deplete GSH and trigger chemodynamic therapy (CDT) simultaneously, further enhancing the oxidative stress. Consequently, the Sub-APL present 2-fold ROS generation under US and 7-fold GSH depletion compared to the discrete Au and POM-LDH mixture. Therefore, the serious imbalance of redox in the TME caused by the sharp increase of ROS and rapid decrease of GSH leads to death of tumor ultimately.

Blunted midbrain reward activation during smoking withdrawal: a preliminary study.

Introduction: Tobacco smoking is the leading preventable cause of death, causing more than six million deaths annually worldwide, mainly due to cardiovascular disease and cancer. Many habitual smokers try to stop smoking but only about 7% are successful, despite widespread knowledge of the risks. Development of addiction to a range of substances is associated with progressive blunting of brain reward responses and sensitisation of stress responses, as described by the allostasis theory of addiction. There is pre-clinical evidence from rodents for a dramatic decrease in brain reward function during nicotine withdrawal. Methods: Here we tested the hypothesis that habitual smokers would also exhibit blunted reward function during nicotine withdrawal using a decision-making task and fMRI. Results: Our findings supported this hypothesis, with midbrain reward-related responses particularly blunted. We also tested the hypothesis that smokers with a longer duration of smoking would have more pronounced abnormalities. Contrary to expectations, we found that a shorter duration of smoking in younger smokers was associated with the most marked abnormalities, with blunted midbrain reward related activation including the dopaminergic ventral tegmental area. Discussion: Given the substantial mortality associated with smoking, and the small percent of people who manage to achieve sustained abstinence, further translational studies on nicotine addiction mechanisms are indicated.

Therapeutic doses of ketamine acutely attenuate the aversive effect of losses during decision-making.

The discovery of rapid-acting antidepressant, ketamine has opened a pathway to a new generation of treatments for depression, and inspired neuroscientific investigation based on a new perspective that non-adaptive changes in the intrinsic excitatory and inhibitory circuitry might underlie the pathophysiology of depression. Nevertheless, it still remains largely unknown how the hypothesized molecular and synaptic levels of changes in the circuitry might mediate behavioral and neuropsychological changes underlying depression, and how ketamine might restore adaptive behavior. Here, we used computational models to analyze behavioral changes induced by therapeutic doses of ketamine, while rhesus macaques were iteratively making decisions based on gains and losses of tokens. When administered intramuscularly or intranasally, ketamine reduced the aversiveness of undesirable outcomes such as losses of tokens without significantly affecting the evaluation of gains, behavioral perseveration, motivation, and other cognitive aspects of learning such as temporal credit assignment and time scales of choice and outcome memory. Ketamine's potentially antidepressant effect was separable from other side effects such as fixation errors, which unlike outcome evaluation, was readily countered with strong motivation to avoid errors. We discuss how the acute effect of ketamine to reduce the initial impact of negative events could potentially mediate longer-term antidepressant effects through mitigating the cumulative effect of those events produced by slowly decaying memory, and how the disruption-resistant affective memory might pose challenges in treating depression. Our study also invites future investigations on ketamine's antidepressant action over diverse mood states and with affective events exerting their impacts at diverse time scales.

Mouse Model of Chronic Social Stress-Induced Excessive Pavlovian Aversion Learning-Memory.

Increased experience of aversive stimuli/events is a psychological-neurobiological state of major importance in psychiatry. It occurs commonly in generalized anxiety disorder, post-traumatic stress disorder, and major depression. A sustained period of exposure to threat (chronic stressor) is a common risk factor, and a major symptom is generalized excessive perception of, and reactivity to, aversive stimuli. In rodents, Pavlovian aversion learning and memory (PAL, PAM), quantified in terms of the conditioned defensive behavior freezing, is an extensively studied behavioral paradigm, and well understood in terms of underlying neural circuitry. In mice, chronic social stress (CSS) is a 15-day resident-intruder paradigm in which C57BL/6 adult males are exposed continuously and distally to dominant-aggressive CD-1 male mice (sustained threat) interspersed with a brief daily period of proximal attack (acute threat). To ensure that physical wounding is minimized, proximal attacks are limited to 30 to 60 s/day and lower incisor teeth of CD-1 mice are blunted. Control (comparison) mice are maintained in littermate pairs. The CSS and CD-1 mice are maintained in distal contact during subsequent behavioral testing. For PAL, CSS and control (CON) mice are placed in a conditioning chamber (context) and exposed to a tone [conditioned stimulus (CS)] and mild, brief foot shock [unconditioned stimulus (US)]. For PAM, mice are placed in the same context and presented with CS repetitions. The CSS mice acquire (learn) and express (memory) a higher level of freezing than CON mice, indicating that CSS leads to generalized hypersensitivity to aversion, i.e., chronic social aversion leads to increased aversion salience of foot shock. Distinctive features of the model include the following: high reproducibility; rare, mild wounding only; male specificity; absence of "susceptible" vs "resilient" subgroups; behavioral effects dependent on continued presence of CD-1 mice; and preclinical validation of novel compounds for normalizing aversion hypersensitivity with accurate feedforward prediction of efficacy in human patients. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Chronic social stress (CSS) Basic Protocol 2: Pavlovian aversion learning and memory (PALM).

No evidence of attentional prioritization for threatening targets in visual search.

Throughout human evolutionary history, snakes have been associated with danger and threat. Research has shown that snakes are prioritized by our attentional system, despite many of us rarely encountering them in our daily lives. We conducted two high-powered, pre-registered experiments (total N = 224) manipulating target prevalence to understand this heightened prioritization of threatening targets. Target prevalence refers to the proportion of trials wherein a target is presented; reductions in prevalence consistently reduce the likelihood that targets will be found. We reasoned that snake targets in visual search should experience weaker effects of low target prevalence compared to non-threatening targets (rabbits) because they should be prioritized by searchers despite appearing rarely. In both experiments, we found evidence of classic prevalence effects but (contrasting prior work) we also found that search for threatening targets was slower and less accurate than for nonthreatening targets. This surprising result is possibly due to methodological issues common in prior studies, including comparatively smaller sample sizes, fewer trials, and a tendency to exclusively examine conditions of relatively high prevalence. Our findings call into question accounts of threat prioritization and suggest that prior attention findings may be constrained to a narrow range of circumstances.

Characterizing positive and negative valence systems function in adolescent depression: An RDoC-informed approach integrating multiple neural measures.

Depression is a prevalent, debilitating, and costly disorder that often manifests in adolescence. There is an urgent need to understand core pathophysiological processes for depression to inform more targeted intervention efforts. The Research Domain Criteria (RDoC) Positive Valence Systems (PVS) and Negative Valence Systems (NVS) have both been implicated in depression symptomatology and vulnerability; however, the nature of NVS alterations is unclear across studies, and associations between single neural measures and symptoms are often small in magnitude and inconsistent. The present study advances characterization of depression in adolescence via an innovative data-driven approach to identifying subgroups of PVS and NVS function by integrating multiple neural measures (assessed by electroencephalogram [EEG]) relevant to depression in adolescents oversampled for clinical depression and depression risk based on maternal history (N = 129; 14-17 years old). Results of the k-means cluster analysis supported a two-cluster solution wherein one cluster was characterized by relatively attenuated reward and emotion responsiveness across valences and the other by relatively intact responsiveness. Youth in the attenuated responsiveness cluster reported significantly greater depressive symptoms and were more likely to have major depressive disorder diagnoses than youth in the intact responsiveness cluster. In contrast, associations of individual neural measures with depressive symptoms were non-significant. The present study highlights the importance of innovative neuroscience approaches to characterize emotional processing in depression across domains, which is imperative to advancing the clinical utility of RDoC-informed research.

Experimental Pain Picture System (EPPS): Development and Validation.

Pain-related pictures are useful for studying how individuals respond to pain-related stimulation. Such pictures can occasionally be found in databases for affective pictures. However, a validated database specifically for pain-related pictures is not available yet. In 2 experiments (N = 185 and 103, respectively), we developed and validated the Experimental Pain Pictures System (EPPS). In both experiments, negative valence, arousal, and painfulness ratings were compared between neutral-, sad-, and pain-related pictures. The pain-related pictures represented both deep and superficial somatic pain. Across the 2 experiments, pain-related pictures were judged as more negative, arousing, and painful than neutral pictures and more painful than sad pictures. The final EPPS contains 50 pictures of different painful events considered moderately to highly painful by participants. The EPPS is a valuable tool for studying pain-related responses, as it gives researchers a choice among many validated pictures depicting different types of pain, increasing the comparability between studies. PERSPECTIVE: This article presents the validation of the experimental pain pictures system, which consists of a set of pain-related pictures. The experimental pain pictures system is composed of pictures depicting different types of pain. Participants rated all the pictures as being negative, arousing, and painful.

Mood and anxiety disorders within the Research Domain Criteria framework of Positive and Negative Valence Systems: a scoping review.

Introduction: While a growing body of research is adopting Research Domain Criteria (RDoC)-related methods and constructs, there is still a lack of comprehensive reviews on the state of published research on Positive Valence Systems (PVS) and Negative Valence Systems (NVS) in mood and anxiety disorders consistent with the RDoC framework. Methods: Five electronic databases were searched to identify peer-reviewed publications covering research on "positive valence" and "negative valence" as well as "valence," "affect," and "emotion" for individuals with symptoms of mood and anxiety disorders. Data was extracted with a focus on disorder, domain, (sub-) constructs, units of analysis, key results, and study design. Findings are presented along four sections, distinguishing between primary articles and reviews each for PVS, NVS, and cross-domain PVS and NVS. Results: A total of 231 abstracts were identified, and 43 met the inclusion criteria for this scoping review. Seventeen publications addressed research on PVS, seventeen on NVS, and nine covered cross-domain research on PVS and NVS. Psychological constructs were typically examined across different units of analysis, with the majority of publications incorporating two or more measures. Molecular, genetic, and physiological aspects were mainly investigated via review articles, primary articles focused on self-report, behavioral, and, to a lesser extent, physiological measures. Conclusions: This present scoping review shows that mood and anxiety disorders were actively studied using a range of genetic, molecular, neuronal, physiological, behavioral, and self-report measures within the RDoC PVS and NVS. Results highlight the essential role of specific cortical frontal brain structures and of subcortical limbic structures in impaired emotional processing in mood and anxiety disorders. Findings also indicate overall limited research on NVS in bipolar disorders and PVS in anxiety disorders, a majority of self-report studies, and predominantly observational studies. Future research is needed to develop more RDoC-consistent advancements and intervention studies targeting neuroscience-driven PVS and NVS constructs.

Behavioral domains in compulsive rats: implications for understanding compulsive spectrum disorders.

Introduction: Compulsive behavior has been proposed as a transdiagnostic trait observed in different neuropsychiatric disorders, such as obsessive-compulsive disorder, autism, and schizophrenia. Research Domain Criteria (RDoC) strategy could help to disentangle the neuropsychological basis of compulsivity for developing new therapeutic and preventive approaches. In preclinical research, the selection of high-drinker (HD) vs. low-drinker (LD) animals by schedule-induced polydipsia (SIP) is considered a putative model of compulsivity, which includes a well-differentiated behavioral pattern. Methods: The purpose of this research was to assess the cognitive control and the negative valence system domains in a phenotype of compulsive HD rats. After the selection of animals as HD or LD, we assessed behavioral inflexibility by probabilistic spatial reversal learning (PSRL), motor and cognitive impulsivity by variable delay-to-signal (VDS), and risky decision-making by rodent gambling task (rGT). Results: HD rats performed fewer reversals and showed less probability of pressing the same lever that was previously reinforced on PSRL, more premature responses after the exposure to longer delays on VDS, and more disadvantageous risky choices on rGT. Moreover, HD animals performed more perseverative responses under the punishment period on rGT. Discussion: These results highlight that HD compulsive phenotype exhibits behavioral inflexibility, insensitivity to positive feedback, waiting impulsivity, risky decision-making, and frustrative non-reward responsiveness. Moreover, these findings demonstrate the importance of mapping different behavioral domains to prevent, treat, and diagnose compulsive spectrum disorders correctly.

Charge-Separated Pdδ--Cuδ+ Atom Pairs Promote CO2 Reduction to C2.

Positively charged Cu sites have been confirmed to significantly promote the production of multicarbon (C2) products from an electrochemical CO2 reduction reaction (CO2RR). However, the positively charged Cu has difficulty in existing under a strong negative bias. In this work, we design a Pdδ--Cu3N catalyst containing charge-separated Pdδ--Cuδ+ atom pair that can stabilize the Cuδ+ sites. In situ characterizations and density functional theory reveal that the first reported negatively charged Pdδ- sites exhibited a superior CO binding capacity together with the adjacent Cuδ+ sites, synergistically promoting the CO dimerization process to produce C2 products. As a result, we achieve a 14-fold increase in the C2 product Faradaic efficiency (FE) on Pdδ--Cu3N, from 5.6% to 78.2%. This work provides a new strategy for synthesizing negative valence atom-pair catalysts and an atomic-level modulation approach of unstable Cuδ+ sites in the CO2RR.

Negative valence system as a relevant domain in compulsivity: review in a preclinical model of compulsivity.

Compulsive behavior is observed in different neuropsychiatric disorders such as Obsessive-Compulsive Disorder (OCD), anxiety, phobia, schizophrenia and addiction. Compulsivity has been proposed as a transdiagnostic symptom, where the Research Domain Criteria (RDoC) strategy could help to understand its neuropsychological basis for a better understanding, and development of therapeutic and preventive strategies. However, research on compulsivity has been focused on the cognitive control domain, and the contribution of an altered negative valence system has been less considered. In this review, we collate the main findings in an animal model of compulsivity, the high drinker (HD) rats selected by Schedule-Induced Polydipsia (SIP) regarding these two research domains. This preclinical model of compulsivity has shown a phenotype characterized by a lack of behavioral inhibition, impulsive decision-making and cognitive inflexibility. Moreover, the results in compulsive HD rats, suggests that there is also a relevant alteration in the emotional dimension, linked to the negative valence system domain, as for example by: the increased perseverative responses in a withdrawal condition, associated with the behavioral construct of frustrative non-reward; and an inhibition or extinction deficit in memory retrieval associated with an alteration in the behavioral response to sustained threat. However, the precise nature of the link between these shared altered domains, cognitive control and negative valence system, remains unknown. These results point towards relevant behavioral aspects of the compulsive phenotype that should be taken into account when studying the vulnerability to compulsivity that could help in the development of a better transdiagnostic assessment, preventive and therapeutic strategies.

The importance of a multidimensional approach to the preclinical study of major depressive disorder and apathy.

Both the neuropsychiatric syndrome of apathy and major depressive disorder comprise a heterogenous cluster of symptoms which span multiple behavioural domains. Despite this heterogeneity, there is a tendency in the preclinical literature to conclude a MDD or apathy-like phenotype from a single dimensional behavioural task used in isolation, which may lead to inaccurate phenotypic interpretation. This is significant, as apathy and major depressive disorder are clinically distinct with different underlying mechanisms and treatment approaches. At the clinical level, apathy and major depressive disorder can be dissociated in the negative valence (loss) domain of the Research Domain Criteria. Symptoms of MDD in the negative valence (loss) domain can include an exaggerated response to emotionally salient stimuli and low mood, while in contrast apathy is characterised by an emotionally blunted state. In this article, we highlight how using a single dimensional approach can limit psychiatric model interpretation. We discuss how integrating behavioural findings from both the positive and negative (loss) valence domains of the Research Domain Criteria can benefit interpretation of findings. We focus particularly on behaviours relating to the negative valence (loss) domain, which may be used to distinguish between apathy and major depressive disorder at the preclinical level. Finally, we consider how future approaches using home cage monitoring may offer a new opportunity to detect distinct behavioural profiles and benefit the overall translatability of findings.

An Examination of the RDoC Negative Valence Systems Domain Constructs and the Self-Reports Unit of Analysis.

In response to shortcomings with the current diagnostic classification system for mental health disorders, such as poor validity and reliability of categorical diagnoses, the National Institute of Mental Health proposed the Research Domain Criteria (RDoC) initiative to move towards a dimensional approach using translational research. The current study examined associations between measures of behaviors, cognitions, and mental health symptoms and how they overlap in the Negative Valence Systems (NVS) domain. Specifically, we examined how the Self-Reports unit of analysis reflects the RDoC NVS constructs of acute threat, potential threat, sustained threat, frustrative nonreward, and loss. The overall goal was to identify additional self-report measures that reflect these constructs. Participants, two student samples and two community samples (total N = 1,509), completed online self-reported measures. Questionnaire total and subscale scores were submitted to a principal-axis factor analysis with Promax rotation separately for each sample. For both student samples and one community sample six-factor solutions emerged reflecting major aspects of the RDoC NVS and positive valence systems, particularly acute threat (i.e., fear/panic), potential threat (i.e., inhibition/worry), sustained threat (i.e., chronic stress), loss (i.e., low well-being), frustrative nonreward (i.e., reactive aggression), and reduced behavioral activation. The second community sample differed in that fear/panic and frustration/anger was combined in a general distress factor. Recommendations for additional NVS self-report markers are discussed.

Abnormal physiological responses toward sensory stimulus are related to the attention deficits in children with sluggish cognitive tempo.

Previous studies have found that sluggish cognitive tempo (SCT) is often associated with difficulties in real-life functioning, such as social problems, emotional difficulties, and academic learning difficulties. However, the underlying mechanisms contributing to the SCT symptoms and its associated real-life difficulties have still not been clearly understood. A previous study has found that SCT symptoms were associated with hypoarousal and hyperarousal toward the sensory stimulus. However, it is still unclear whether such abnormal arousal regulation is related to sustained attention difficulties that have been found to be related to social difficulties and withdrawn behavior in children with SCT. In this study, arousal regulation deficit in SCT is examined by the physiological responses quantified by HRV and EEG in the sensory challenge paradigm. This study aimed to establish a linkage between arousal regulation reflected by HRV and EEG and attention difficulties in children with SCT. The results of this study showed that higher theta power in the auditory stimulation condition than in the resting condition was associated with higher omission errors in sustained attention tasks in the SCT group. It was also found that higher parasympathetic activities during sensory stimulation conditions were associated with higher commission errors in the SCT group. These results reflected that hypersensitivity toward stressful sensitivity toward a stressful sensory stimulus is associated with attention difficulties in children with SCT. This further supported the notion that SCT should be conceptualized as a condition characterized by multiple deficits in different biological systems, such as the cognitive system, the negative valence system, and the arousal regulatory system.

Detecting negative valence symptoms in adolescents based on longitudinal self-reports and behavioral assessments.

BACKGROUND: Given the high prevalence of depressive symptoms reported by adolescents and associated risk of experiencing psychiatric disorders as adults, differentiating the trajectories of the symptoms related to negative valence at an individual level could be crucial in gaining a better understanding of their effects later in life. METHODS: A longitudinal deep learning framework is presented, identifying self-reported and behavioral measurements that detect the depressive symptoms associated with the Negative Valence System domain of the NIMH Research Domain Criteria (RDoC). RESULTS: Applied to the annual records of 621 participants (age range: 12 to 17 years) of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), the deep learning framework identifies predictors of negative valence symptoms, which include lower extraversion, poorer sleep quality, impaired executive control function and factors related to substance use. LIMITATIONS: The results rely mainly on self-reported measures and do not provide information about the underlying neural correlates. Also, a larger sample is required to understand the role of sex and other demographics related to the risk of experiencing symptoms of negative valence. CONCLUSIONS: These results provide new information about predictors of negative valence symptoms in individuals during adolescence that could be critical in understanding the development of depression and identifying targets for intervention. Importantly, findings can inform preventive and treatment approaches for depression in adolescents, focusing on a unique predictor set of modifiable modulators to include factors such as sleep hygiene training, cognitive-emotional therapy enhancing coping and controllability experience and/or substance use interventions.

Valence processing alterations in SAPAP3 knockout mice and human OCD.

Abnormalities in valence processing - the processing of aversive or appetitive stimuli - may be an underrecognized component of obsessive-compulsive disorder (OCD). Preclinical rodent models have been critical in furthering pathophysiological understanding of OCD, yet there is a dearth of investigations examining whether rodent models of compulsive behavior show alterations in valence systems congruent with those seen in individuals with OCD. In this study, we sought to assess valence processing in a preclinical rodent model of compulsive behavior, the SAPAP3 knockout (KO) mouse model, and compare our preclinical findings to similar behavioral phenomena in OCD patients. In SAPAP3 KO mice, we used auditory fear conditioning and extinction to examine alterations in negative valence processing and reward-based operant conditioning to examine alterations in positive valence processing. We find that SAPAP3 KO mice show evidence of heightened negative valence processing through enhanced fear learning and impaired fear extinction. SAPAP3 KO mice also show deficits in reward acquisition and goal-directed behavior, suggesting impaired positive valence processing. In OCD patients, we used validated behavioral tests to assess explicit and implicit processing of fear-related facial expressions (negative valence) and socially-rewarding happy expressions (positive valence). We find similar trends towards enhanced negative and impaired positive valence processing in OCD patients. Overall, our results reveal valence processing abnormalities in a preclinical rodent model of compulsive behavior similar to those seen in OCD patients, with implications for valence processing alterations as novel therapeutic targets across a translational research spectrum.

Sex-Specific Neural Networks of Cued Threat Conditioning: A Pilot Study.

Cued threat conditioning is the most common preclinical model for emotional memory, which is dysregulated in anxiety disorders and post-traumatic stress disorder. Though women are twice as likely as men to develop these disorders, current knowledge of threat conditioning networks was established by studies that excluded female subjects. For unbiased investigation of sex differences in these networks, we quantified the neural activity marker c-fos across 112 brain regions in adult male and female mice after cued threat conditioning compared to naïve controls. We found that trained females engaged prelimbic cortex, lateral amygdala, cortical amygdala, dorsal peduncular cortex, and subparafasicular nucleus more than, and subparaventricular zone less than, trained males. To explore how these sex differences in regional activity impact the global network, we generated interregional cross-correlations of c-fos expression to identify regions that were co-active during conditioning and performed hub analyses to identify regional control centers within each neural network. These exploratory graph theory-derived analyses revealed sex differences in the functional coordination of the threat conditioning network as well as distinct hub regions between trained males and females. Hub identification across multiple networks constructed by sequentially pruning the least reliable connections revealed globus pallidus and ventral lateral septum as the most robust hubs for trained males and females, respectively. While low sample size and lack of non-associative controls are major limitations, these findings provide preliminary evidence of sex differences in the individual circuit components and broader global networks of threat conditioning that may confer female vulnerability to fear-based psychiatric disease.

Modeling heritability of temperamental differences, stress reactivity, and risk for anxiety and depression: Relevance to research domain criteria (RDoC).

Animal models provide important tools to study biological and environmental factors that shape brain function and behavior. These models can be effectively leveraged by drawing on concepts from the National Institute of Mental Health Research Domain Criteria (RDoC) Initiative, which aims to delineate molecular pathways and neural circuits that underpin behavioral anomalies that transcend psychiatric conditions. To study factors that contribute to individual differences in emotionality and stress reactivity, our laboratory utilized Sprague-Dawley rats that were selectively bred for differences in novelty exploration. Selective breeding for low versus high locomotor response to novelty produced rat lines that differ in behavioral domains relevant to anxiety and depression, particularly the RDoC Negative Valence domains, including acute threat, potential threat, and loss. Bred Low Novelty Responder (LR) rats, relative to their High Responder (HR) counterparts, display high levels of behavioral inhibition, conditioned and unconditioned fear, avoidance, passive stress coping, anhedonia, and psychomotor retardation. The HR/LR traits are heritable, emerge in the first weeks of life, and appear to be driven by alterations in the developing amygdala and hippocampus. Epigenomic and transcriptomic profiling in the developing and adult HR/LR brain suggest that DNA methylation and microRNAs, as well as differences in monoaminergic transmission (dopamine and serotonin in particular), contribute to their distinct behavioral phenotypes. This work exemplifies ways that animal models such as the HR/LR rats can be effectively used to study neural and molecular factors driving emotional behavior, which may pave the way toward improved understanding the neurobiological mechanisms involved in emotional disorders.